Cellular Plasticity and HPA Axis Dysfunction

细胞可塑性和 HPA 轴功能障碍

• 批准号: 6897437
• 负责人: JEFFREY G TASKER
• 金额: $ 32.69万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6897437
• 关键词: chronic disease /disorder; corticotropin releasing factor; depression; electrophysiology; gamma aminobutyrate; glucocorticoids; glutamates; hormone regulation /control mechanism; hypothalamic pituitary adrenal axis; laboratory rat; neural plasticity; neuroanatomy; neurons; neurophysiology; norepinephrine; paraventricular nucleus; receptor expression; stress; voltage /patch clamp

DESCRIPTION (provided by applicant): Chronic stress and depression lead to a sustained increase in the activation of the hypothalamic-pituitary adrenal (HPA) axis and tonically elevated levels of circulating HPA hormones, including glucocorticoids. Sequelae of chronic stress in experimental models and in humans include hypersensitivity of the HPA axis to stressful stimuli, and reduced sensitivity of the HPA axis to negative feedback regulation by circulating glucocorticoids. Likely causes of the chronic stress-induced hypersensitivity of the HPA axis and sustained hypersecretion of HPA hormones is an increased excitatory synaptic drive to and a reduced sensitivity to glucocorticoids of the cells that trigger HPA axis activation, the corticotropin releasing hormone (CRH) neurons of the paraventricular nucleus (PVN). Synaptic activation of the CRH neurons appears to involve an interaction between glutamatergic, GABAergic and noradrenergic systems, suggesting that structural changes in these systems may be responsible for the altered responsiveness of the HPA axis during chronic stress and depression. Rapid feedback inhibitory actions of glucocorticoids appear to be mediated, in part, by activation of endocannabinoid release within the PVN and a resulting retrograde suppression of glutamate release onto the PVN CRH neurons. Through a collaborative network of investigators studying the HPA axis, we have acquired preliminary anatomical and molecular data to suggest that the synaptic innervation of PVN CRH neurons is structurally altered by exposure to chronic stress. This proposal is the cellular physiology component of an IRPG application designed to address the overarching hypothesis that chronic stress leads to long-term molecular, anatomical and functional changes in the synaptic circuitry and glucocorticoid feedback that regulate PVN CRH neurons and the hypothalamic response to stress. We will use whole-cell patch-clamp recordings and genomic analyses to determine whether exposure to chronic stress causes an increase in the excitability of PVN CRH neurons 1) by altering glutamatergic, GABAergic and/or noradrenergic synaptic inputs, and/or 2) by reducing glucocorticoid inhibitory feedback regulation. These studies will provide important insight into the functional changes that occur in the brain during chronic stress, and will offer potential targets for the clinical treatment of certain stress-related affective disorders, such as severe depression.

描述（由申请人提供）：慢性压力和抑郁会导致下丘脑-垂体肾上腺 (HPA) 轴的激活持续增加，以及循环 HPA 激素（包括糖皮质激素）水平的紧张性升高。实验模型和人类中慢性应激的后遗症包括 HPA 轴对应激刺激的超敏性，以及 HPA 轴对循环糖皮质激素负反馈调节的敏感性降低。慢性压力诱发的 HPA 轴超敏反应和 HPA 激素持续分泌过多的可能原因是触发 HPA 轴激活的细胞（促肾上腺皮质激素释放激素 (CRH) 神经元）的兴奋性突触驱动增加和对糖皮质激素的敏感性降低。室旁核（PVN）。 CRH 神经元的突触激活似乎涉及谷氨酸能、GABA 能和去甲肾上腺素能系统之间的相互作用，表明这些系统的结构变化可能是慢性应激和抑郁期间 HPA 轴反应性改变的原因。糖皮质激素的快速反馈抑制作用似乎部分是通过激活 PVN 内的内源性大麻素释放以及由此产生的对 PVN CRH 神经元上谷氨酸释放的逆行抑制来介导的。通过研究 HPA 轴的研究人员协作网络，我们获得了初步的解剖学和分子数据，表明 PVN CRH 神经元的突触神经支配因暴露于慢性压力而发生结构改变。该提案是 IRPG 应用程序的细胞生理学组成部分，旨在解决以下总体假设：慢性应激会导致突触回路和糖皮质激素反馈发生长期分子、解剖和功能变化，从而调节 PVN CRH 神经元和下丘脑对应激的反应。我们将使用全细胞膜片钳记录和基因组分析来确定暴露于慢性应激是否会导致 PVN CRH 神经元兴奋性增加 1) 通过改变谷氨酸能、GABA 能和/或去甲肾上腺素能突触输入，和/或 2) 通过减少糖皮质激素抑制反馈调节。这些研究将为慢性压力期间大脑发生的功能变化提供重要的见解，并将为某些与压力相关的情感障碍（例如严重抑郁症）的临床治疗提供潜在的目标。